CD69+ Vδ1γδ T cells are anti-tumor subpopulations in hepatocellular carcinoma.

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC), one of the malignancies with a wide expression of stress ligands recognized by Vδ1γδ T cells, has received much attention in adoptive immunotherapy of γδ T cells. In this study, we aimed to identify the potential anti-tumor Vδ1γδ T subpopulations in HCC. METHODS: Healthy donors (HDs) and HCC patients were recruited from the Affiliated Cancer Hospital of Zhengzhou University. Blood and tumor tissue samples were obtained respectively. Bioinformatics methods were used to analyze total γδ T cells and subsets infiltration, overall survival of HCC patients with high and low infiltration level of Vδ1γδ T cells, and IFNG, granzyme A, granzyme B and perforin expression in TRDV1high/lowCD69high/low groups. CD69 expression and Vδ1γδT cells infiltration in HCC were detected by immunofluorescence. Phenotypic analysis of Vδ1γδ T cells in blood and tumor tissue samples were performed by flow cytometry. RESULTS: Vδ1γδ T cells infiltrating in HCC were associated with better clinical outcome. Study in tumor micro-environment (TME) of HCC demonstrated that not total Vδ1γδ T but CD69+ Vδ1γδ subset infiltration was associated with smaller tumor volume. Moreover, HCC patients simultaneously with high TRDV1 and CD69 expression produced more effector molecules and had longer survival time. Since Vδ1γδ T cells in the tumor microenvironment were often difficult to access, we demonstrated that CD69+ Vδ1γδ T cells also existed in peripheral blood mononuclear cells (PBMC) of HCC and displayed enhanced cytotoxic potentials than HDs. Finally, we investigated the functions and found that CD69+ Vδ1γδ T cells exhibited stronger tumor reactivities when challenged by tumor cells. CONCLUSIONS: CD69+ Vδ1γδ T cells are functional Vδ1γδ T cell subsets in patients with HCC. Circulating CD69+ Vδ1γδ T cell is a promising candidate in immunotherapy of HCC.

Modes of Nanodroplet Formation and Growth on an Ultrathin Water Film.

Using nanobubbles as geometrical confinements, we create a thin water film (∼10 nm) in a graphene liquid cell and investigate the evolution of its instability at the nanoscale under transmission electron microscopy. The breakdown of the water films, resulting in the subsequent formation and growth of nanodroplets, is visualized and generalized into different modes. We identified distinct droplet formation and growth modes by analyzing the dynamic processes involving 61 droplets and 110 liquid bridges within 31 Graphene Liquid Cells (GLCs). Droplet formation is influenced by their positions in GLCs, taking on a semicircular shape at the edge and a circular shape in the middle. Growth modes include liquid mass transfer driven by Plateau-Rayleigh instability and merging processes in and out-of-plane of the graphene interface. Droplet growth can lead to the formation of liquid bridges for which we obtain multiview projections. Data analysis reveals the general dynamics of liquid bridges, including drawing liquids from neighboring residual water films, merging with surrounding droplets, and merging with other liquid bridges. Our experimental observations provide insights into fluid transport at the nanoscale.

An EBV-related CD4 TCR immunotherapy inhibits tumor growth in an HLA-DP5+ nasopharyngeal cancer mouse model.

Adoptive transfer of T cell receptor-engineered T cells (TCR-T) is a promising strategy for immunotherapy against solid tumors. However, the potential of CD4+ T cells in mediating tumor regression has been neglected. Nasopharyngeal cancer is consistently associated with EBV. Here, to evaluate the therapeutic potential of CD4 TCR-T in nasopharyngeal cancer, we screened for CD4 TCRs recognizing EBV nuclear antigen 1 (EBNA1) presented by HLA-DP5. Using mass spectrometry, we identified EBNA1567-581, a peptide naturally processed and presented by HLA-DP5. We isolated TCR135, a CD4 TCR with high functional avidity, that can function in both CD4+ and CD8+ T cells and recognizes HLA-DP5-restricted EBNA1567-581. TCR135-transduced T cells functioned in two ways: directly killing HLA-DP5+EBNA1+ tumor cells after recognizing EBNA1 presented by tumor cells and indirectly killing HLA-DP5-negative tumor cells after recognizing EBNA1 presented by antigen-presenting cells. TCR135-transduced T cells preferentially infiltrated into the tumor microenvironment and significantly inhibited tumor growth in xenograft nasopharyngeal tumor models. Additionally, we found that 62% of nasopharyngeal cancer patients showed 50%-100% expression of HLA-DP on tumor cells, indicating that nasopharyngeal cancer is well suited for CD4 TCR-T therapy. These findings suggest that TCR135 may provide a new strategy for EBV-related nasopharyngeal cancer immunotherapy in HLA-DP5+ patients.

Cytokine-induced killer (CIK) cells, successes and challenges: report on the first international conference dedicated to the clinical translation of this unique adoptive cell immunotherapy.

On August 30, 2023, experts from Germany and abroad met to discuss the successes and challenges of cytokine-induced killer cell (CIK) therapy, that recently celebrated its 30th anniversary providing treatment for cancer. This first virtual conference was hosted by CIO Bonn, a certified Comprehensive Cancer Center (CCC) funded by German Cancer Aid (DKH). In addition to keynote speakers involved in CIK cell clinical trials or optimized preclinical models to improve this adoptive cell immunotherapy, more than 100 attendees from around the world also participated in this event. Initiatives to establish the International Society of CIK Cells (ISCC) and a stronger CIK cell network guiding preclinical research and future clinical trials were also announced.

The inter-link of ageing, cancer and immunity: findings from real-world retrospective study.

BACKGROUND: Although the concept of declined immune function associated with cancer has been accepted extensively, real-world clinical studies focusing on analysis of the peripheral blood immune changes underlying ageing, immunity and cancer are scarce. METHODS: In this case-control study, we retrospectively analysed 1375 cancer patients and enrolled 275 age and gender matched healthy individuals. Flow cytometry was conducted to assess the immune changes. Further analysis was examined by SPSS 17.0 and GraphPad Prism 9 software. RESULTS: Cancer patients showed obviously decreased CD3+ T, CD3+CD4+ Th, CD3+CD8+ CTL, CD19+ B, CD16+CD56+ NK cell counts and lower percentage of PD-1 (programmed cell death protein-1, PD-1) positive cells than healthy control (P < 0.0001). For cancer patients, the reference range of circulating percentage of PD-1+CD45+ cells, PD-1+CD3+ T cells, PD-1+CD3+CD4+ Th cells and PD-1+CD3+CD8+ CTL (Cytotoxic T Lymphocyte, CTL) were 11.2% (95% CI 10.8%-11.6%), 15.5% (95% CI 14.7%-16.0%), 15.4% (95% CI 14.9%-16.0%) and 14.5% (95% CI 14.0%-15.5%), respectively. Moreover, the reduction of CD3+ T, CD3+CD4+ Th, CD3+CD8+ CTL, CD19+ B cell counts accompanied with age and stage advancing (P < 0.05). CD16+CD56+ NK cells decreased with stage, but elevated in aged and male cancer patients (P < 0.05). Additionally, the percentage of PD-1 positive cells varied across cancer types, raised with age and stage. Head and neck, pancreatic, gynaecological and lung demonstrated a higher level of the percentage of PD-1 positive cells than melanoma, prostate, and breast cancer (P < 0.05). CONCLUSIONS: This study provides the reference range of the percentage of PD-1 positive cells on peripheral blood, confirms the decreased immune cells and a series of immune changes accompanying with cancer, expands our real world evidence to better understand the interactions of ageing, cancer and immunity. Moreover, the circulating percentage of PD-1 positive cells shows similar tumor type distribution with tumor mutational burden (TMB), supports that it maybe a potential predictive biomarker for immune checkpoint inhibitor therapy.

Adjusting the dose of traditional drugs combined with immunotherapy: reshaping the immune microenvironment in lung cancer.

Immunotherapy is currently the most promising clinical treatment for lung cancer, not only revolutionizing second-line therapy but now also approved for first-line treatment. However, its clinical efficiency is not high and not all patients benefit from it. Thus, finding the best combination strategy to expand anti-PD-1/PD-L1-based immunotherapy is now a hot research topic. The conventional use of chemotherapeutic drugs and targeted drugs inevitably leads to resistance, toxic side effects and other problems. Recent research, however, suggests that by adjusting the dosage of drugs and blocking the activation of mutational mechanisms that depend on acquired resistance, it is possible to reduce toxic side effects, activate immune cells, and reshape the immune microenvironment of lung cancer. Here, we discuss the effects of different chemotherapeutic drugs and targeted drugs on the immune microenvironment. We explore the effects of adjusting the dosing sequence and timing, and the mechanisms of such responses, and show how the effectiveness and reliability of combined immunotherapy provide improved treatment outcomes.

Low-dose anlotinib confers improved survival in combination with immune checkpoint inhibitor in advanced non-small cell lung cancer patients.

BACKGROUND: Anti-angiogenic drugs increase anti-tumor efficacy of immune checkpoint inhibitors (ICIs). However, the optimal dose of anti-angiogenic drugs remains unclear. METHODS: We retrospectively analyzed efficacy and safety data from patients diagnosed with advanced or metastatic non-small cell lung cancer (NSCLC) that received PD-1 blockade with low-doses of anlotinib, a highly selective receptor tyrosine kinase inhibitor mainly targeting vascular endothelial growth factor receptors, as second or later line therapy. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), overall response rate (ORR), disease control rate (DCR), and safety profile. Univariate and multivariate analyses were used to identify prognostic factors. RESULTS: A total of 40 eligible patients were included. The median PFS was 11.4 months. The median OS of the entire cohort was 27.0 months. ORR was achieved in 16 patients (40.0%) and DCR was maintained in 33 patients (82.5%). The overall incidence of adverse events (AEs) was 52.5%, and the most common all grade AE was gastrointestinal reactions, which occurred in four patients (10.0%). Treatment-related grade 3/4 toxicity was observed in one patient (2.5%). Conclusions Low-dose anlotinib may be an effective and well-tolerated anti-angiogenesis partner for combination therapy with ICIs in second-line and later settings for advanced NSCLC.

Association of hepatitis B virus DNA levels with overall survival for advanced hepatitis B virus-related hepatocellular carcinoma under immune checkpoint inhibitor therapy.

BACKGROUND: High hepatitis B virus (HBV) DNA level is an independent risk factor for postoperative HBV-associated liver cancer recurrence. We sought to examine whether HBV DNA level and antiviral therapy are associated with survival outcomes in patients with advanced hepatocellular carcinoma (HCC) treated with anti-programmed cell death protein 1 (PD-1)based immunotherapy. METHODS: This single-institution retrospective analysis included 217 patients with advanced HBV-related HCC treated from 1 June 2018, through 30 December 2020. Baseline information was compared between patients with low and high HBV DNA levels. Overall survival (OS) and progression-free survival (PFS) were compared, and univariate and multivariate analyses were applied to identify potential risk factors for oncologic outcomes. RESULTS: The 217 patients included in the analysis had a median survival time of 20.6 months. Of these HBV-associated HCC patients, 165 had known baseline HBV DNA levels. Baseline HBV DNA level was not significantly associated with OS (P = 0.59) or PFS (P = 0.098). Compared to patients who did not receive antiviral therapy, patients who received antiviral therapy had significantly better OS (20.6 vs 11.1 months, P = 0.020), regardless of HBV DNA levels. Moreover, antiviral status (adjusted HR = 0.24, 95% CI 0.094-0.63, P = 0.004) was an independent protective factor for OS in a multivariate analysis of patients with HBV-related HCC. CONCLUSIONS: HBV viral load does not compromise the clinical outcome of patients with HBV-related HCC treated with anti-PD-1-based immunotherapy. The use of antiviral therapy significantly improves survival time of HBV-related HCC patients.

A two-pronged strategy to alleviate tumor hypoxia and potentiate photodynamic therapy by mild hyperthermia.

The application of photodynamic therapy (PDT) is limited by tumor hypoxia. To overcome hypoxia, catalase-like nanozymes are often used to catalyze endogenous H2O2 enriched in tumor tissues to O2. Nonetheless, the catalase activity may not be optimal at body temperature and the O2 supply may not meet the rapid O2 consumption of PDT. Herein, we provide a two-pronged strategy to alleviate tumor hypoxia based on hollow mesoporous Prussian blue nanoparticles (HMPB NPs). HMPB NPs can efficiently load the photosensitizer chlorin e6 (Ce6) and exhibit photothermal capability and temperature-dependent catalase activity. Under 808 nm laser irradiation, the photothermal effect of HMPB NPs elevated the catalase activity of HMPB NPs for O2 production. Furthermore, mild hyperthermia reduced cancer associated fibroblasts (CAFs) and induced extracellular matrix (ECM) degradation. The reduction of CAFs and the ECM decreased the solid stress of tumor tissues and normalized the tumor vasculature, which was beneficial for the external supplementation of O2 to tumors. Thereafter, under 606 nm laser irradiation, Ce6-mediated PDT generated excessive reactive oxygen species (ROS) that induced tumor cell apoptosis and achieved a high tumor inhibition rate of 92.2% in 4T1 breast tumors. Our work indicated that the alleviation of tumor hypoxia from both internal and external pathways significantly enhanced Ce6-mediated PDT against breast cancers.

In vivo growth of subclones derived from Lewis lung carcinoma is determined by the tumor microenvironment.

Heterogeneity is a fundamental feature of human tumors and plays a major role in drug resistance and disease progression. In the present study, we selected single-cell-derived cell lines (SCDCLs) derived from Lewis lung carcinoma (LLC1) cells to investigate tumorigenesis and heterogeneity. SCDCLs were generated using limiting dilution. Five SCDCLs were subcutaneously injected into wild-type C57BL/6N mice; however, they displayed significant differences in tumor growth. Subclone SCC1 grew the fastest in vivo, whereas it grew slower in vitro. The growth pattern of SCC2 was the opposite to that of SCC1. Genetic differences in these two subclones showed marked differences in cell adhesion and proliferation. Pathway enrichment results indicate that signal transduction and immune system responses were the most significantly altered functional categories in SCC2 cells compared to those in SCC1 cells in vitro. The number and activation of CD3+ and CD8+ T cells and NK cells in the tumor tissue of tumor-bearing mice inoculated with SCC2 were significantly higher, whereas those of myeloid cells were significantly lower, than those in the SCC1 and LLC1 groups. Our results suggest that the in vivo growth of two subclones derived from LLC1 was determined by the tumor microenvironment rather than their intrinsic proliferative cell characteristics.

Sintilimab maintenance therapy post first-line cytokine-induced killer cells plus chemotherapy for extensive-stage small cell lung cancer.

Despite recent progress in treating advanced non-small cell lung cancer, clinical intervention in extensive-stage small-cell lung cancer (ES-SCLC) remains stagnant. The purpose of this study was to evaluate the clinical efficacy of cytokine-induced killer (CIK) cells combined with cytotoxic chemotherapy, followed by anti-programmed death 1 antibody (sintilimab) maintenance, in ES-SCLC patients. To explore a new method for safe treatment of ES-SCLC patients, thirteen ES-SCLC patients were enrolled between June 2019 and December 2021. All patients received first-line chemotherapy (etoposide plus platinum) combined with CIK cell therapy. Patients who reached a stable disease state or responded well to treatment received sintilimab maintenance treatment. The primary objective of this study was to determine the median overall survival (OS); the secondary objective was to assess the objective response rate (ORR), progression-free survival 1 and 2 (PFS1 was defined as the duration from the signing of informed consent to the date of tumor progression, or death, or the last follow-up. PFS2 was defined as the duration from the first day of sintilimab treatment to the date of tumor progression, death, or the last follow-up.), and adverse reactions. At a 24.1-month follow-up, the median OS was 11.8 (95% confidence interval [CI]: 10.6-13.0) months, median PFS1 was 5.5 (95% CI: 5.0-6.0) months, and the median PFS2 was 2.3 (95% CI: 0.5-4.1) months. The ORR was 76.9% (10/13), the disease control rate was 100% (13/13), and the 20-month survival rate was 41.7%. Eight participants exhibited grade 3 or 4 adverse events after combination therapy. During maintenance treatment with sintilimab, level 3 adverse events occurred in 1 patient (1/9). In conclusion, adding CIK cells to standard chemotherapy regimens, followed by maintenance therapy with sintilimab, may represent a new safe and effective treatment strategy. Clinical trial registration: ClinicalTrials.gov (NCT03983759).

Combination of Low-Dose Gemcitabine and PD-1 Inhibitors for Treatment in Patients With Advanced Malignancies.

Purpose: This study determined the efficacy of low-dose gemcitabine combined with programmed death-1 (PD-1) inhibitors for treating multiple malignancies, providing a cost-effective and safe treatment option. Study Design: This study included 61 patients with advanced solid tumors treated with low-dose gemcitabine combined with PD-1 inhibitors at the Henan Cancer Hospital between January 2018 and February 2022. We retrospectively reviewed medical records to evaluate several clinical factors, including progression-free survival (PFS), overall survival (OS), adverse effects (AEs), and objective response to treatment. Results: Sixty-one patients received treatment with low-dose gemcitabine combined with PD-1 inhibitors. The objective response rate (ORR) was 29.5% and the disease control rate (DCR) was 62.3%. The median PFS was 4.3 months (95% confidence interval, 2.3 to 6.3 months) and the median OS was 15.0 months (95% confidence interval, 8.8 to 21.2 months). Hematological toxicity, mainly leukopenia or thrombocytopenia, was the most common AE, with any-grade and grade 3/4 hematological toxicity reported in 60.7 and 13.1% of patients, respectively. Conclusions: Low-dose gemcitabine combined with PD-1 inhibitors may offer a novel treatment option for patients with advanced malignancies.

Efficacy and Safety of Apatinib in Patients with Recurrent or Refractory Melanoma.

BACKGROUND: The prognosis of patients with metastatic malignant melanoma is very poor and partly due to resistance to conventional chemotherapies. The study's objectives were to assess the activity and tolerability of apatinib, an oral small molecule anti-angiogenesis inhibitor, in patients with recurrent advanced melanoma. METHODS: This was a single-arm, single-center phase II trial. The primary endpoint was progression-free survival (PFS) and the secondary endpoints were objective response rate (ORR), disease control rate (DCR), and overall survival (OS). Eligible patients had received at least one first-line therapy for advanced melanoma and experienced recurrence. Apatinib (500 mg) was orally administered daily. RESULTS: Fifteen patients (V660E BRAF status: 2 mutation, 2 unknown, 11 wild type) were included in the analysis. The median PFS was 4.0 months. There were two major objective responses, for a 13.3% response rate. Eleven patients had stable disease, with a DCR of 86.7%. The median OS was 12.0 months. The most common treatment-related adverse events of any grade were hypertension (80.0%), mucositis oral (33.3%), hand-foot skin reaction (26.7%), and liver function abnormalities, hemorrhage, diarrhea (each 20%). The only grade ≥3 treatment-related adverse effects that occurred in 2 patients was hypertension (6.7%) and mucositis (6.7%). No treatment-related deaths occurred. CONCLUSION: Apatinib showed antitumor activity as a second- or above-line therapy in patients with malignant melanoma. The toxicity was manageable. CLINICALTRIALS.GOV IDENTIFIER: NCT03383237.

Identification of an immune gene-associated prognostic signature in patients with bladder cancer.

A deeper understanding of the interaction between tumor cell and the immune microenvironment in bladder cancer may help select predictive and prognostic biomarkers. The current study aims to construct a prognostic signature for bladder cancer by analysis of molecular characteristics, as well as tumor-immune interactions. RNA-sequencing and clinical information from bladder cancer patients were downloaded from the TCGA database. The single sample Gene Sets Enrichment Analysis (ssGSEA) and Cell type Identification by Estimating Relative Subsets of RNA Transcripts (CIBERSORT) were employed to separate the samples into two clusters. Lasso Cox regression was performed to construct an immune gene signature for bladder cancer. The correlation between key target genes of immune checkpoint blockade and the prognostic signature was also analyzed. Dataset from Gene Expression Omnibus (GEO) was retrieved for validation. Two immunophenotypes and immunological characteristics were identified, and a 17-immune gene signature was constructed to provide an independent prognostic signature for bladder cancer. The signature was verified through external validation and correlated with genomic characteristics and clinicopathologic features. Finally, a nomogram was generated from the clinical characteristics and immune signature. Our study reveals a tumor-immune microenvironment signature useful for prognosis in bladder cancer. The results provide information on the potential development of treatment strategies for bladder cancer patients. Prospective studies are warranted to validate the prognostic capability of this model, but these data highlight the role of the microenvironment in the clinical outcome of patients.

Tumor-specific activatable biopolymer nanoparticles stabilized by hydroxyethyl starch prodrug for self-amplified cooperative cancer therapy.

Rationale: Chemodynamic therapy (CDT) is an emerging tumor-specific therapeutic strategy. However, the anticancer activity of CDT is impeded by the insufficient Fenton catalytic efficiency and the high concentration of glutathione (GSH) in the tumor cells. Also, it is challenging to eliminate tumors with CDT alone. Thus, simple strategies aimed at constructing well-designed nanomedicines that can improve therapeutic efficiency of CDT and simultaneously incorporate extra therapeutic modes as helper are meaningful and highly required. Method: Tailored to specific features of tumor microenvironment (TME), in this study, we developed a biosafe, stable and TME-activated theranostic nanoplatform (P(HSD-Cu-DA)) for photoacoustic imaging (PAI) and self-amplified cooperative therapy. This intelligent nanoplatform was fabricated following a simple one-pot coordination and polymerization strategy by using dopamine and Cu2+ as precursors and redox-responsive hydroxyethyl starch prodrugs (HES-SS-DOX) as stabilizer. Results: Interestingly, the pre-doped Cu2+ in polydopamine (PDA) framework can endow P(HSD-Cu-DA) NPs with tumor-specific CDT ability and remarkably enhance NIR absorption of PDA. PAI and biodistribution tests proved such nanoplatform can effectively accumulate in tumor tissues. Following enrichment, massive amounts of toxic hydroxyl radicals (·OH, for CDT) and free DOX (for chemotherapy) were generated by the stimulation of TME, which was further boosted by local hyperthermia. Concomitantly, in the process of activating these therapeutic functions, GSH depletion triggered by disulfide bond (-SS-) breakage and Cu2+ reduction within tumor cells occurred, further amplifying intratumoral oxidative stress. Importantly, the framework structure dominated by bioinspired polydopamine and clinical-used HES guaranteed the long-term biosafety of in vivo treatment. As a result, the mutual promotion among different components yields a potent tumor suppression outcome and minimized systemic toxicity, with one dosage of drug administration and laser irradiation, respectively. Conclusion: This work provides novel insights into designing efficient and tumor-specific activatable nanotherapeutics with significant clinical translational potential for cancer therapy.

Role of fibrosarcoma-induced CD11b+ myeloid cells and tumor necrosis factor-α in B cell responses.

The role of B cells in the anti-tumor immune response remains controversial. An increase in the number of B cells in the peripheral blood of some tumor patients has been associated with poor immunotherapy efficacy. However, the mechanism leading to the generation of these cells is not well-described. Using a fibrosarcoma model, we show that intraperitoneal administration of a xenogeneic antigen in tumor-bearing mice evokes large increases in antigen-specific serum immunoglobulin formation compared to tumor-naïve mice. An inability of tumor-bearing mice to induce enhanced antibody production after myeloid cell depletion suggests the antibody responses are CD11b+ myeloid cell-dependent. In vitro, CD11b+ myeloid cells promoted B cell proliferation, activation, and survival. High levels of tumor necrosis factor (TNF)-α were produced by CD11b+ cells, and TNF-α blockade inhibited B cell responses. CD11b+ cells appear to be important promoters of B cell responses and targeting B cells may increase the efficacy of immunotherapy in tumor-bearing hosts.

Novel immunotherapeutic drugs for the treatment of lung cancer.

PURPOSE OF REVIEW: Cancer cells evade immune surveillance partly due to the immunosuppressive features of the tumor microenvironment (TME). Currently approved immuno-oncology drugs for the treatment of lung cancer are aimed to inhibit immune checkpoints, such as programmed death protein-1 (PD-1), PD ligand-1 (PD-L1) and cytotoxic T lymphocyte-associated antigen 4. Despite these, researchers are currently racing to create the optimal cancer immunotherapy treatments. RECENT FINDINGS: Novel immunotherapeutic drugs mainly act on activated immune cells and exert their therapeutic effects by enhancing antitumor responses. In this article, we review new therapies for the treatment of lung cancer that enhance T cell priming, remove coinhibitory signals, supply costimulatory signals and condition the TME. SUMMARY: As more immunotherapeutic targets are in studies, designing multimodal strategies to provide greater efficacy with lower toxicity will be necessary.

The Sequence of Chemotherapy and Toripalimab Might Influence the Efficacy of Neoadjuvant Chemoimmunotherapy in Locally Advanced Esophageal Squamous Cell Cancer-A Phase II Study.

Background: There is no standard neoadjuvant therapy for locally advanced esophageal cancer in China. The role of neoadjuvant chemotherapy plus immunotherapy for locally advanced esophageal cancer is still being explored. Methods: This open-label, randomized phase II study was conducted at a single center between July 2019 and September 2020; 30 patients with locally advanced esophageal squamous cell carcinoma (ESCC) (T3, T4, or lymph-node positive) were enrolled. Patients were randomized according to the enrollment order at a 1:1 ratio to receive chemotherapy on day 1 and toripalimab on day 3 (experimental group) or chemotherapy and toripalimab on day 1 (control group). The chemotherapeutic regimen was paclitaxel and cisplatin. Surgery was performed 4 to 6 weeks after the second cycle of chemoimmunotherapy. The primary endpoint was pathological complete response (pCR) rate, and the secondary endpoint was safety and disease-free survival. Results: Thirty patients completed at least one cycle of chemoimmunotherapy; 11 in the experimental group and 13 in the control group received surgery. R0 resection was performed in all these 24 patients. Four patients (36%) in the experimental group and one (7%) in the control group achieved pCR. The experimental group showed a statistically non-significant higher pCR rate (p = 0.079). PD-L1 combined positive score (CPS) examination was performed in 14 patients; one in the control group had a PD-L1 CPS of 10, and pCR was achieved; the remaining 13 all had ≤1, and 11 of the 13 patients received surgery in which two (in the experimental group) achieved pCR. Two patients endured ≥grade 3 adverse events, and one suffered from grade 3 immune-related enteritis after one cycle of chemoimmunotherapy and dropped off the study. Another patient died from severe pulmonary infection and troponin elevation after surgery. Conclusions: Although the primary endpoint was not met, the initial results of this study showed that delaying toripalimab to day 3 in chemoimmunotherapy might achieve a higher pCR rate than that on the same day, and further large-sample clinical trials are needed to verify this. Clinical Trial Registration: ClinicalTrials.gov, identifier NCT03985670.

Toxic Epidermal Necrolysis-Like Reaction Following Combination Therapy With Camrelizumab and Apatinib for Advanced Gallbladder Carcinoma.

Recently, combination regimens based on programmed cell death-1 (PD-1) blockade have become increasingly common in clinical practice for the treatment of cancer. Such combinations significantly improve efficacy, but treatment-related adverse events have also become more complex and severe. Here, we report an acute toxic epidermal necrolysis (TEN)-like reaction in a patient with gallbladder cancer who received camrelizumab (an anti-PD-1 antibody) in combination with apatinib. Interestingly, distinct clinical and pathological characteristics were observed that differed from those of the reported cases of severe cutaneous reactions induced by anti-PD-1 antibodies alone; thus, we speculate that it was induced by the combination of camrelizumab and apatinib. It is worth noting that the TEN-like reaction showed resistance to methylprednisolone initially, which was gradually resolved after the addition of intravenous immunoglobulin (IVIg). Immunohistochemical staining revealed that the skin lesion was infiltrated by moderate numbers of CD4+ T cells and large numbers of CD8+ T cells during the progression of the TEN-like reaction, and mass cytometry by time-of-flight showed a significant reduction in the CD4+ and CD8+ T cell proportions in the peripheral blood after the rash improved. All these findings highlight the essential role of CD4+ T cells and CD8+ T cells in the TEN-like reaction induced by camrelizumab plus apatinib treatment, and we speculate that T cells, especially CD8+ T cells, attack keratinocytes. In conclusion, the TEN-like reaction induced by camrelizumab and apatinib deserves clinical attention, and further work is needed to elucidate the exact pathophysiologic mechanism as well as the optimal management strategy.